Tamoxifen Metabolism and CYP2D6

Systemic tamoxifen has been the standard approach for reducing risk of recurrence in women with estrogen receptor (ER)–positive early-stage breast cancer for more than 40 years. Long-term data have demonstrated that the use of tamoxifen reduces recurrence and mortality by more than 30% in both premenopausal and postmenopausal women, regardless of the use of systemic chemotherapy. ^[1] Aromatase inhibitors (AIs), such as anastrozole (Arimidex) and exemestane (Aromasin), have been proven to be as effective as, or superior to, tamoxifen. AIs have been utilized as initial adjuvant therapy, as sequential therapy followed by 2-3 years of tamoxifen, or as an extended therapy following 4.5-6 years of tamoxifen. ^[2]

Endoxifen, the principal metabolite of tamoxifen, is subject to a high interindividual variability in serum concentration. A study by Braal et al showed that key predictors of endoxifen concentration were CYP2D6 genotype, age and weight. CYP2D6 genotype explained 54% of the variability, and 3% could be explained by age and weight. ^[3]  Tamoxifen is metabolized via CYP2D6 into endoxifen (4-OH-N-desmethyl-tamoxifen), its primary active metabolite. Multiple investigations have identified genetic variants of CYP2D6 that can affect its activity, which in turn affects the metabolism of tamoxifen. The proficiency with which CYP2D6 metabolizes tamoxifen was assumed to be associated with the specific variant of the gene that an individual possesses, on the basis of studies that were conducted in breast cancer patients taking selective serotonin reuptake inhibitors (SSRIs) to relieve hot flashes. ^{[4, 5, 6]}

Specifically, because SSRIs inhibit CYP2D6, significantly lower endoxifen concentrations were also found in the studies’ patients. Further analysis identified 3 different groups of patients on the basis of genetic variants of CYP2D6: patients with 2 wild-type (wt), or normal, alleles; those with 1 non-wt allele; and those with 2 non-wt alleles. In a direct dose-gene effect, patients with 2 non-wt alleles had lower concentrations of endoxifen than did those with 1 non-wt allele, and patients with 2 wt alleles had endoxifen levels similar to those of poor metabolizers of tamoxifen who were not taking SSRIs. ^{[5, 6]}  Follow-up studies identified the *4 variant (1846G>A) as the most common allele associated with poor metabolism of tamoxifen. ^{[7, 8]}

A retrospective study conducted by Goetz et al showed that patients with the CYP2D6*4/*4 genotype had significantly shorter relapse-free time (RFT) and disease-free survival (DFS) time than did patients with *4/wt and wt/wt variants, although no difference was seen in overall survival. ^[7] In addition, patients who were poor metabolizers, defined as those with *4/*4 alleles or patients on strong CYP2D6 inhibitors for 2-3 years, had significantly shorter time to recurrence, significantly worse RFT, and significantly higher risk of relapse than did patients with wt alleles and those not on CYP2D6 inhibitors. ^[9]

Results from a study of patients enrolled in a Stockholm Breast Cancer Group clinical trial showed that tamoxifen-treated patients with at least 1 CYP2D6*4 allele had a significantly better survival time than did those without the genetic variant. ^[10]

The polymorphism has more than 100 known alleles, and based on genotype combinations, these are commonly classified into 4 phenotypes ^[11] :

• Ultra-rapid metabolizers (UM)
• Extensive (normal) metabolizers (EM)
• Intermediate metabolizers (IM)
• Poor metabolizers (PM) 

Prediction of an impaired tamoxifen metabolizer phenotype (IM, PM) with low endoxifen formation capacity is potentially important for personalized treatment decisions in breast cancer, such as increasing the therapeutic dose or replacing tamoxifen with an AI. ^[12]  Comprehensive CYP2D6 genotyping panels can be helpful to guide treatment decisions for nonmetastatic ER-positive breast cancer patients, and alternatives to standard tamoxifen treatments may be considered in patients who are CYP2D6 poor or intermediate metabolizers. ^[13]

Among the most influential studies of the association between CYP2D6 genotype and tamoxifen effectiveness are the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and the Breast International Group (BIG) 1-98 trials, which together randomized more than 9000 patients to tamoxifen or to anastrozole or letrozole, respectively. ^{[14, 15]}

In both assessments, CYP2D6 allele status had no effect on any outcomes, including disease recurrence, distant recurrence, and overall survival. ^{[16, 17]} In addition, because it was thought that the presence of hot flashes might be an indicator of metabolic activity of tamoxifen, BIG 1-98 investigators also looked at whether the presence or absence of hot flashes might correlate with CYP2D6 allele status. Again, no difference was seen between the groups. ^[17]

Nevertheless, the question of whether CYP2D6 allele status influences outcomes from tamoxifen still remains. Critics of these assessments have challenged the inconsistent use of somatic versus germline DNA in testing for genetic mutations and possible deviations from accepted statistical methodology. ^[18] Indeed, a matched case-control study using data from the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that corrected for these factors found significant differences in disease recurrence in patients taking tamoxifen for 5 years, although the difference was not apparent in patients taking only 2-3 years of tamoxifen who were then switched to anastrozole. ^[9]

It has been suggested that the current data may be suspect because of poor understanding of the metabolism of tamoxifen and endoxifen within the cytochrome P450 pathway. ^[18]

Ongoing studies of patients with metastatic breast cancer that are incorporating genetic testing will add more information to the debate, ^[19] but it is unclear whether they will fully resolve the question of how and whether CYP2D6 allele status influences outcomes from tamoxifen therapy given in the adjuvant setting.

The International Tamoxifen Pharmacogenomics Consortium (ITPC) is compiling comprehensive information on CYP2D6 and other genetic variants associated with metabolism and effects of tamoxifen in women treated with tamoxifen for breast cancer. ^{[20, 21, 22, 23]}

Low-dose tamoxifen has been shown to decrease recurrence by 50% in cases of noninvasive breast cancer without significant adverse events. DeCensi et al studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a trial of low-dose tamoxifen. Endoxifen was below 9 nM in most patients treated with 5 mg/day, despite strong efficacy, and there was no association with recurrence, suggesting that the reason for tamoxifen failure was not poor drug metabolism. ^[24]

The National Comprehensive Cancer Network (NCCN) does not recommend testing for CYP2D6 variants in patients considering tamoxifen in the adjuvant setting, which matches the recommendation from the American Society of Clinical Oncology (ASCO) about not testing for CYP2D6 variants in patients considering tamoxifen as a breast cancer risk reduction strategy. ^{[2, 25, 26]}  

There is evidence that SSRIs paroxetine and fluoxetine interfere with the enzymatic conversion of tamoxifen to endoxifen by inhibiting a particular isoform of CYP2D6. The NCCN guidelines recommend that medications that have minimal or no impact on plasma levels of endoxifen should be substituted whenever possible. ^[2] These alternatives include citalopram, venlafaxine, and escitalopram. ^[27]

The Clinical Pharmacogenetic Implementation Consortium (CPIC) has made recommendations based on phenotype, including the following ^[28] :

• CYP2D6 ultrarapid metabolizers and normal metabolizers are expected to achieve therapeutic endoxifen concentrations after administration of tamoxifen and should receive the recommended standard dose of tamoxifen, 20 mg/day. ^[28]
• CYP2D6 poor metabolizers and intermediate metabolizers are expected to have lower endoxifen concentrations compared to normal metabolizers and have a higher risk of breast cancer recurrence, as well as worse event-free survival. For CYP2D6 poor metabolizers, a “strong” therapeutic recommendation was provided to recommend alternative hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype and based on knowledge that CYP2D6 poor metabolizers who switch from tamoxifen to anastrozole do not exhibit an increased risk of recurrence. ^[28]
• Given that escalation of tamoxifen dose from 20 mg/day to 40 mg/day in CYP2D6 poor metabolizers significantly increases endoxifen concentrations (but not to concentrations achieved in CYP2D6 normal metabolizers), the use of an aromatase inhibitor (+/− ovarian function suppression) is recommended. ^[28]

The European Society for Medical Oncology (ESMO) Guidelines Committee made recommendations for postmenopausal patients that include the following ^[29] :

• The use of tamoxifen is associated with an increased risk of thromboembolic complications and endometrial hyperplasia (including a small risk of endometrial cancer). Caution should be exercised in patients with risk factors for these conditions, and appropriate diagnostic tests should be carried out in the presence of symptoms suggestive of these complications. Patients on tamoxifen should be advised to avoid the use of strong and moderate CYP2D6 inhibitors (although there are no unequivocal data on their detrimental effects). If such drugs cannot be replaced, a switch to alternative treatment (ie, aromatase inhibitors) should be considered. ^[29]
• The study of CYP2D6 polymorphisms as a decision aid regarding the use of adjuvant tamoxifen is not proven and should not be done outside a clinical trial. ^[29]